U.S. Acts to Make Vaccines and Drugs Against Smallpox

Even as a team of investigators descends on Florida in response to a death from anthrax, it is smallpox that has many experts losing sleep.

Ancient and vicious, the virus killed more people over the ages than any other infectious disease, up to 500 million in the 20th century alone. Unlike anthrax, it is highly contagious, able to spread like fire through a dry forest. And unlike anthrax, which must be prepared to very strict specifications to do its lethal work, striking the initial spark with smallpox requires no special tricks or knowledge. In theory, anyone who could obtain the virus could ignite a global epidemic.

Experts say the chances of terrorists' laying hands on a stock of the virus are very low, so low that some do not even list smallpox on their roster of terrorist threats. But given the potential consequences of an outbreak, the government is taking a number of steps to counter an attack with the virus.

It has quietly embarked on new studies to see if existing stocks of old smallpox vaccine -- an estimated 7 million to 15 million doses -- can be diluted to stretch the stockpile. It also just announced plans to speed up production of a new vaccine, to make 40 million doses available next year. The ultimate goal is to have enough vaccine for all Americans. Meanwhile, researchers are looking into new antiviral drugs to fight the disease in unvaccinated people.

Eradicated two decades ago, smallpox no longer exists in nature or human populations, unlike most pathogens that can be used as weapons. Officially, only the United States and Russia have stocks of the virus, under tight security.

But federal experts suspect that clandestine supplies of the virus exist and are taking no chances.

''When you see two wonderful cities with buildings going down, that heightens the urgency,'' Dr. Anthony S. Fauci, the government's top infectious disease expert, said. ''This is simply the prudent thing to do, to be prepared for anything.''

In a nod to the smallpox threat, Health and Human Services Secretary Tommy G. Thompson has named Dr. Donald A. Henderson, the man who led the global effort to eradicate smallpox, as chairman of his new bioterrorism advisory panel. Dr. Henderson, dean emeritus of the Johns Hopkins School of Public Health, in recent years has called for rebuilding global stockpiles of smallpox vaccine as a hedge against biological attacks.

The risk, Dr. Henderson said in an interview, ''is small but it's not zero, and the result can be catastrophic.'' He added that he found the dilution studies heartening. Now, he said, health officials have ''some of this in hand to make the vaccine supply go considerably farther.''

Smallpox is a disease of high fevers, deep rashes, bloody sores and oozing pustules that extend from head to foot. It spreads from person to person in the air, and people exposed to it show symptoms in about two weeks. Roughly one in three victims die. Once people begin experiencing symptoms, they can spread the virus to others. Death occurs from blood loss, cardiovascular collapse and secondary infections.

Most Americans are considered vulnerable. The United States stopped routine vaccinations of civilians against smallpox in 1972, nearly a decade ahead of much of the world. People born since then are unprotected. For vaccinated people, the degree of security is unclear because scientists never systematically measured the length of immunity. Protection drops with time, but how much is unknown.

Today, family doctors have no access to the existing vaccine stockpile, which the government keeps for emergencies. Its size is inexact because the number of doses depends partly on the skill of the vaccinators, who don't give a shot but instead must lightly puncture the skin. The government says it would not reinstitute routine immunization even if supplies were unlimited because of the vaccine's occasional side effects.

Before the advent of vaccination, the best protection was catching and surviving the disease in childhood, which gave lifetime immunity. During the Revolutionary War, British soldiers often had immunity and rebellious Americans often did not.

Elizabeth Anne Fenn, a historian at George Washington University, in a new book, ''Pox Americana: The Great Smallpox Epidemic of 1775-82,'' shows how George Washington was deeply suspicious of British smallpox attacks as the disease ravaged his troops.

A British officer, she noted, recommended that arrows dipped in smallpox matter be shot at American rebels to ''disband these stubborn, ignorant, enthusiastic savages.''

Vaccination, invented in 1796, let doctors infect patients with a kindred but usually benign virus (cowpox at first, vaccinia later) that gave smallpox immunity. In countries with good medical care, the disease slowly ebbed, making its occasional returns all the more frightening.

One occurred in 1947, when an American businessman was admitted to Bellevue Hospital with what doctors thought was an extremely bad case of chickenpox.

''We had no idea,'' recalled Florence Berger Adler, who as a 22-year-old student nurse cared for the man on his admittance. ''He was critically ill. The whites of his eyes were bright red and he was disoriented. All he did was moan.''

As it turned out, the man had picked up smallpox on a trip to Mexico; before doctors realized what was happening, he had infected at least a dozen New Yorkers. In the ensuing panic, health authorities vaccinated (or revaccinated) six million people, including the student nurse. The vaccine works unusually fast, saving a person even three or four days after the start of viral infection.

Eventually, a global campaign of vaccination cornered the virus, and public health authorities in 1980 declared it extinct in humans, its only natural reservoir. All samples of the virus were to be destroyed or sent to central repositories. But eradication leaders had no powers of inspection. They had only diplomatic assurances when, one by one, nations said the virus was gone.

After the cold war, evidence mounted that smallpox endured beyond the two official repositories. Russian defectors told how Moscow had built secret factories to annually make up to 100 tons of the virus for weapons. As the Soviet empire collapsed, Western experts feared that stolen germs might fall into unfriendly hands.

By 1998, a secret United States intelligence report concluded that Iraq, North Korea and Russia were probably concealing the smallpox virus for possible military use.

That same year, Dr. Henderson, the eradication pioneer, began calling for new vaccine production to deal with a deliberate release of the virus. ''Its potential for devastation today is far greater than at any previous time,'' he and 14 other smallpox experts wrote in the June 9, 1999, issue of The Journal of the American Medical Association. ''In a now highly susceptible, mobile population, smallpox would be able to spread widely and rapidly throughout this country and the world.''

While drawing up plans for a new smallpox vaccine, Washington quietly investigated if the nation's existing supply of up to 15 million doses could be diluted to one-hundredth of its original strength in an emergency.

The research began in early 2000 at Saint Louis University. Three groups of 20 volunteers got either undiluted vaccine, tenfold dilutions or hundredfold dilutions. Scientists judged the effect on the basis of blood studies and looking at vaccinated arms for characteristic boils and scabs.

Dr. Fauci, director of the National Institute of Allergy and Infectious Diseases, said last week that the success rate of highly diluted vaccine was found to be ''very low,'' but that the tenfold dilution was about 70 percent effective.

In response to the Sept. 11 attacks, he added, his institute is now embarking on a new round of dilution studies with a total of 650 volunteers. The studies are to be done at Saint Louis University, the University of Rochester, the University of Maryland and the Baylor College of Medicine. The new dilutions will be tenfold and fivefold, a level the researchers expect to be highly effective.

Dr. Caroline Hall, a professor of pediatrics and infectious diseases at the University of Rochester medical school, said the vaccinations were to begin fairly soon, with the results known by December, so health authorities would understand the options ''if we need to have more vaccine in a hurry.''

Fivefold dilution would expand the potential 15 million doses to 75 million doses, or about a quarter of the nation's population.

Though it was once used globally, the old vaccine is considered barely acceptable for human use today because its manufacturing method -- infecting calves with the kindred virus and gathering up the resulting pus -- inevitably produced microbial contamination. The new vaccine is to be grown in human cells suspended in large tanks known as bioreactors, and will be purer. Even so, thousands of human volunteers will be needed to test its safety and efficacy.

The Centers for Disease Control and Prevention in Atlanta placed a $343 million order for 40 million doses of new vaccine last fall, with a delivery date of 2004. Jonathan B. Tucker, author of ''Scourge,'' a book about smallpox, said the order's size was based on a federal computer simulation of how much vaccine would be needed if the smallpox virus appeared in an American city and spread beyond.

The contractor is Acambis, a British company. Its American subsidiary, based in Cambridge, Mass., is to make the vaccine. The scientific chief of the American team is Thomas P. Monath, a top virologist and recently chairman of a high-level group that advised the Central Intelligence Agency on ways to counter the spread of weapons of mass destruction.

In an interview, a production official who spoke on the condition of anonymity said the speedup of first deliveries from 2004 to 2002 would be done by ''working harder and longer,'' and by securing new cooperation from drug regulators. The 40 million doses will be ready before clinical trials are complete, he said, and if needed the vaccine can be made available under rules for ''investigational new drugs'' which allow drugs to be used before trials are complete.

The contract calls for regular vaccine deliveries through 2020. Rather than discarding expired lots, the C.D.C. plans to store them indefinitely since the vaccine seems to retain its potency almost indefinitely. Over two decades, Acambis is to make a total of 168 million doses.

In theory, scientists say, the new vaccine may also be found suitable for dilution, making perhaps as many as 200 million doses available as soon as next year if needed.

The federal plan is to stockpile the vaccine at secret locations for national emergencies, rather than dispensing it for routine vaccinations. Some experts are now questioning that policy.

An argument against routine administration is that the vaccine is not without medical risk. Historically, it produced adverse reactions in roughly 1 in 13,000 vaccinated people, the complications ranging from severe rashes to encephalitis, or inflammation of the brain. Roughly one in one million people died.

Today, experts say, the danger may be higher because more people are surviving with immune systems weakened by conditions like leukemia, lymphoma and infection with the virus that causes AIDS. Pregnant women and people with eczema are also considered vulnerable.

To develop protections beyond the vaccine, dozens of scientists around the country are now investigating new antiviral drugs that, if perfected, could treat groups at special risk of vaccine complications and perhaps even save disease victims.

''People here in the labs, after Sept. 11, are working with a sense of urgency,'' said Dr. Mark Buller, a virologist at Saint Louis University, who directs a team investigating smallpox treatments. ''There's nothing absolute now. There's no such thing as absolute safety.''

Although the virus would be simple to disseminate (the government in 1965 did a clandestine test at an airport in which sprayers spread mock germs), many experts say no nation possessing the virus would give it to a terrorist because of the danger of starting a global epidemic that would kill indiscriminately.

''Societies that harbor terrorists might be at greater risk than we are,'' said a top federal adviser on biological terrorism, who spoke on the condition of anonymity.

Dr. Tucker, an expert on biological and chemical weapons at the Monterey Institute of International Studies, has argued that even Saddam Hussein, whom he calls ''ruthless but not reckless,'' would be highly unlikely to hand over the virus to terrorists if he had it.

Still, some medical professionals question that logic and are pressing for routine vaccinations. The student nurse of 1947, Mrs. Adler, now 77 and living in Altamonte Springs, Fla., said American health authorities should vaccinate as soon as possible coast to coast.

''With the terrorists,'' she said, ''who knows what they'll do next?''